KR20140050609A - Methods for preventing toxic drug-drug interactions in combination therapies comprising anti-erbb3 agents - Google Patents

Abstract

Drugs toxic during combination cancer therapy with drugs that are tyrosine kinase inhibitors and / or drugs that bind alpha-1 acid glycoproteins (eg, erlotinib), to drugs that are anti-ErbB3 agents, such as anti-ErbB3 antibodies- Methods of preventing drug interactions are described. Health care physicians who obtain all of these drugs co-administer anti-ErbB3 agents with one or both of a drug that is a tyrosine kinase inhibitor and a drug that binds to alpha-1 acid glycoprotein. At least one of the drugs to be administered is warned to be administered using a reduced dose to prevent toxicity. At reduced doses, the amount of drug administered per unit time is reduced compared to the dose to be administered when the drug is administered as monotherapy. The reduced dose may be, for example, a reduced drug dosage or a reduced frequency of drug administration, or both. Compositions useful for practicing the described methods are also provided.

Description

METHODS FOR PREVENTING TOXIC DRUG-DRUG INTERACTIONS IN COMBINATION THERAPIES COMPRISING ANTI-ERBB3 AGENTS}

Drugs toxic during combination cancer therapy with drugs that are tyrosine kinase inhibitors and / or drugs that bind alpha-1 acid glycoproteins (eg, erlotinib), to drugs that are anti-ErbB3 agents, such as anti-ErbB3 antibodies- Methods of preventing drug interactions are described. Health care physicians who obtain all of these drugs co-administer anti-ErbB3 agents with one or both of a drug that is a tyrosine kinase inhibitor and a drug that binds to alpha-1 acid glycoprotein. At least one of the drugs to be administered is warned to be administered using a reduced dose to prevent toxicity. At reduced doses, the amount of drug administered per unit time is reduced compared to the dose to be administered when the drug is administered as monotherapy. The reduced dose may be, for example, a reduced drug dosage or a reduced frequency of drug administration, or both. Compositions useful for practicing the described methods are also provided.

Excessive signaling activity mediated by cell surface ErbB / HER family receptors, eg due to receptor overexpression, is characteristic of many types of tumor cells. Such excessive signaling is understood to promote the expression of malignant cell phenotypes. The present understanding has allowed the development of therapeutic therapies to treat cancers by targeting and decreasing signaling activity mediated by these receptors. For example, tyrosine kinase inhibitors (TKIs), such as erlotinib (eg , erlotinib hydrochloric acid, Tarceva®) and zefitinib (Iressa®), express this activity. It specifically inhibits the cleavage-induced tyrosine kinase activity of certain ErbB / HER receptors and thereby is useful for the treatment of various cancers.

An approach in which a single drug is administered to treat a disease or disorder in the absence of the administration of other therapeutic agents administered to treat the same disease or disorder (eg, a therapeutic monoclonal antibody to treat cancer) is called monotherapy. Is mentioned. In the treatment of cancers, co-administration of multiple anticancer drugs (combination therapy) often provides better results than monotherapy. Many drugs are known to alter the bioavailability of other drugs when both drugs are co-administered. For example, certain drugs can alter the degree of plasma protein binding of other drugs. If the amount of the first drug in the bloodstream of the patient that binds to a plasma protein, such as serum albumin or alpha 1-acid glycoprotein (AAG), is changed (e.g., by combination therapy with the second drug), the first Bioavailability in the bloodstream of the drug is also altered thereby.

When the first drug increases the bioavailability of the second drug, the increased exposure to the resulting second drug may be toxic. As new drugs are first used in combination therapies, unexpected and risky toxic drug-drug interactions can be observed. It is important for physicians to avoid causing these drug-drug interactions (DDIs) because the resulting toxicities can lead to significant morbidity and mortality.

Anti-ErbB3 agents (eg, Antibodies) constitute a new class of anticancer drugs, at least three of which are currently undergoing clinical trials in human cancer patients.

Thus, there is a need for approaches to safely administer new combination therapies for cancer treatment, including administration of anti-ErbB3 agents. Such approaches include compositions and methods that prevent or reduce the toxicity resulting from such combination therapies and provide other benefits.

This application claims priority to US Provisional Application No. 61 / 483,195 (filed May 6, 2011), which is incorporated by reference in its entirety for either and all purposes.

Methods are provided for reducing the risk of harmful drug-drug interactions when supplying or administering drugs for combination therapy methods. These methods involve a combination of therapeutic agents that are not anti-ErbB3 agents and additional anti-ErbB3 agents. In one embodiment, the additional therapeutic agent binds to a tyrosine kinase inhibitor (TKI) or the plasma protein, alpha 1-acid glycoprotein, and provides sufficient binding affinity for such binding to alter the bioavailability of the drug in the bloodstream of the patient. Eggplant is one of two drugs (AAG binder-hereafter "AAGB"). AAG binding drugs are also described in US Pat. No. 5,750,493. Many TKIs are AAGBs. Erlotinib and gefitinib are therefore (non-limiting) examples of both TKIs and AAGBs. Other examples of TKIs known to be AAGBs include imatinib and lapatinib.

As disclosed in the examples below, administration of an anti-ErbB3 agent to patients who received co-administration (at the manufacturer's recommended dose) of TKI, which is AAGB, was administered to patients receiving the same dose of TKI as monotherapy. It has been observed to increase the frequency of observation of signs and / or symptoms of toxicity associated with TKIs when compared to the frequency of these signs and / or symptoms observed in. It is further observed that increasing the dose of anti-ErbB3 agent further increases the frequency of observation of signs and / or symptoms of toxicity associated with TKIs in these patients. It is also observed that in many patients who exhibit signs and / or symptoms of such TKI toxicity, the plasma levels of TKI are higher than those of patients who do not exhibit these signs and symptoms.

These observations indicate that anti-ErbB3 agents and drugs that are TKI and / or AAGB induce drug-drug interactions that can produce signs and symptoms of toxicity. In one aspect, it is believed that the plasma concentration of free AAGB (unbound with plasma proteins) is increased by co-administration of AAGB and anti-ErbB3 antibodies. In another aspect, it is believed that the total plasma concentration of TKI (eg, AUC) is increased by co-administration of TKI with an anti-ErbB3 antibody.

Accordingly, provided herein are methods and compositions that allow co-administration of such drug combinations while reducing deleterious drug-drug interactions.

The feeding methods described herein include the following:

The TKI or AAGB is supplied in a container containing a) a TKI or AAGB formulated for administration to the patient, and b) a written or printed warning to the healthcare professional, the warning being given by the TKI or AAGB with an ErbB3 inhibitor. When co-administered to the patient, providing a TKI or AAGB to the drug distributor indicating that a dose reduction of the TKI or AAGB should be considered.

ErbB3 inhibitors are supplied in containers containing a) an ErbB3 inhibitor formulated for administration to a patient, and b) a written or printed warning to a healthcare professional, the warning being given to the patient with an ErbB3 inhibitor along with TKI or AAGB. When co-administered, supplying an ErbB3 inhibitor to the drug distributor, indicating that a dose reduction of TKI or AAGB should be considered.

The TKI is supplied in a container containing a) a TKI formulated for administration to the patient, and b) a written or printed warning to the healthcare professional, the warning being given to the patient to co-administer the TKI with the ErbB3 inhibitor. When providing a TKI to the drug distributor, indicating that a dose reduction of the TKI should be considered.

AAGB is supplied in a container containing a) AAGB formulated for administration to a patient, and b) a written or printed warning to the healthcare professional, the warning being the AAGB co-administered to the patient with an ErbB3 inhibitor. When feeding AAGB to the drug distributor, indicating that a dose reduction of AAGB should be considered.

In certain embodiments of the respective warnings in the four preceding paragraphs, the warning indicates that the reduction for the patient who is a smoker should be of a smaller magnitude reduction than for the patient who is not a smoker.

ErbB3 inhibitors are supplied in containers containing a) an ErbB3 inhibitor formulated for administration to a patient, and b) a written or printed warning to a healthcare professional, the warning being given to the patient with a drug whose ErbB3 inhibitor is AAGB. When co-administered, it is indicated that a dose reduction of AAGB should be considered, or a warning indicates that a dose reduction of ErbB3 inhibitor should be considered when co-administered to a patient with a drug whose ErbB3 inhibitor is AAGB. Instructing a drug distributor to supply an ErbB3 inhibitor.

In preferred embodiments, the recorded or printed alert is a recorded audio alert, a recorded video alert, a recorded alert in computer readable form, or a printed alert, printed drawings, printed barcode (s), printed One or more such as QR (rapid response) code (s) and the like.

In other embodiments, the medical professional is a doctor, physician assistant, nurse, pharmacist or pharmacist technician; TKI or AAGB is erlotinib or zefitinib, and the warning further indicates that a dose reduction of 50 mg increments or 25 mg increments is suggested; TKI or AAGB is erlotinib or zefitinib, and the warning further indicates that a dose reduction of 125 mg increments or about 62 mg increments is suggested; TKI or AAGB is zefitinib and the warning further indicates that a dose reduction consisting of administering the drug every other day, not every day, is suggested; The patient suffers from cancer in which treatment with either or both of TKI or AAGB is indicated; And the patient suffers from cancer in which treatment with an ErbB3 inhibitor is indicated, and the ErbB3 inhibitor is an anti-ErbB3 antibody, including but not limited to all of those described below, including MM-121 or AMG888.

Thus, in one aspect, as a therapeutic method for preventing toxic DDI derived from combination therapy treatment of anti-ErbB3 agents and cancer patients with TKI or AAGB, the first TKI or AAGB dose is administered with the co-administered anti-ErbB3 agent. Recommended by the manufacturer of TKI or AAGB for the administration of TKI or AAGB in the absence, and the second TKI or AAGB dose is the manufacturer of TKI or AAGB for the administration of TKI or AAGB in the presence of co-administered anti-ErbB3 agents or Recommended by the distributor or suggested for consideration, the second dose being a reduced dose that provides a reduced dose of TKI or AAGB compared to the first dose; A method is provided, comprising co-administering a TKI and an anti-ErbB3 agent with a TKI administered to a cancer patient according to a reduced dose.

In another aspect, as a method for combination therapy, the therapy is for the treatment of patients suffering from cancer, and the combination therapy is an anti-ErbB3 drug and a tyrosine kinase inhibitor (TKI) drug or alpha 1-acid glycoprotein binding (AAGB A) a dose of both of the drugs, and either or both of 1) a TKI drug or an AAGB drug, and 2) an anti-ErbB3 drug to the patient, either at a modified dosage or at a modified frequency of administration, or A method is provided, comprising administering both an anti-ErbB3 drug and a TKI drug or AAGB drug, which are administered in both.

In various aspects, each modified dosage of the drug may be a reduced dosage compared to the dosage recommended for monotherapy treatment with the drug in such patients (eg, monotherapy dosage). In various embodiments, the TKI drug or AAGB drug is administered at a reduced dose and the anti-ErbB3 drug is not administered at the reduced dose; ErbB3 drug is administered at a reduced dose and TKI drug or AAGB drug is not administered at a reduced dose; Each 1) TKI drug or AAGB drug and 2) anti-ErB3 drug are administered at a reduced dosage; The amount of each dose is reduced to 10-75%; The frequency of administration of the at least one drug is reduced compared to the frequency of administration recommended for the at least one drug; TKI drug or AAGB drug is administered at reduced frequency, and anti-ErbB3 drug is not administered at reduced frequency; ErbB3 drugs are administered at reduced frequency, TKI drugs or AAGB drugs are not administered at reduced frequency; Each 1) TKI drug or AAGB drug and 2) anti-ErB3 drug are administered at reduced frequency; Each reduced frequency is obtained by extending the intervals between administrations to at least daily; And

Anti-ErbB3 drug shows first serum half-life;

TKI drug or AAGB drug shows a second serum half-life; And

Administration to the patient of the anti-ErbB3 drug occurs within the first serum half-lives 1 to 3 times prior to administration of the TKI drug or AAGB drug;

Administration of the anti-ErbB3 drug occurs within second serum half-lives 1 to 3 times prior to administration of the TKI drug or AAGB drug.

In one embodiments of each of the methods described above, the reduced dose comprises reducing the amount of AAGB or TKI administered at each dose (each time zone in which AAGB or TKI was administered). In this embodiment, each dosage is 1/10, 1/8, 1/6, 1/5, 1/4, 1/3, 1 / compared to each dosage of each first dose. 2, 2/3 or 3/4, or up to about 10, 25, 50, 100, 150, 200, 250, 300, 400, 425, 500, or 750 mg. In still other embodiments of each of the methods described above, the reduced dose comprises reducing the frequency of administration of the doses of AAGB or TKI. In further embodiments of each of the methods described above, the reduced dose comprises reducing both the amount of each dose of AAGB or TKI and the frequency of administration.

In non-limiting embodiments of each of the methods described above, the anti-ErbB3 formulation inhibits phosphorylation of ErbB3 when ErbB3 is contacted with heregulin (eg, in vitro ). In other non-limiting embodiments, the anti-ErbB3 agent is TKI, eg lapatinib. In other non-limiting embodiments, the anti-ErbB3 agent is a monospecific anti-ErbB3 antibody. In one such embodiment, the anti-ErbB3 agent is a monoclonal anti-ErbB3 antibody MM-121 or with MM-121 for binding to ErbB3, as described in US Pat. No. 7,846,440 (as "Ab # 6"). It is a competing antibody. In another such embodiment, the anti-ErbB3 antibodies are all other anti-ErbB3 antibodies described in US Pat. No. 7,846,440, such as Ab # 3, Ab # 14, Ab # 17 or Ab # 19, or do not bind to ErbB3. In order to compete with Ab # 3, Ab # 14, Ab # 17 or Ab # 19. Additional examples of anti-ErbB3 antibodies that may be administered according to the methods described herein include US patents and patent publications 7,285,649; US20100310557; And antibodies described in 20100255010, as well as, for example, antibodies 1B4C3 and 2D1D12 (U3 Pharmasa AG) described in US Patent Publications 20040197332, but are not limited to AMG888 (U3-1287-U3). Anti-ErbB3 antibodies described in US Pat. No. 7,705,130, including anti-ErbB3 antibodies referred to as Pharmasa AG and Amgen, and monoclonal antibodies such as 8B8 described in US Pat. No. 5,968,511 (humanized versions thereof) And the like). Other such examples include anti-ErbB3 antibodies that are multi-specific antibodies and comprise anti-ErbB3 linked to at least a second antibody. For example, such multispecific antibodies can be bispecific antibodies, such as antibodies comprising anti-ErbB3 antibodies linked with a second antibody, such as an anti-IGFR1 antibody. In one embodiment, the bispecific antibody is as described in International Patent Application No. PCT / US2009 / 040259 (published as WO 2009/126920) (eg, “B2B3-1” or “B2B3-2”). ), Anti-ErbB3 antibodies linked with anti-ErbB3 antibodies. Other suitable bispecific anti-ErbB3 agents are also described herein. Monospecific anti-ErbB3 antibodies can be administered in therapeutically effective doses, such as monotherapy doses.

In other embodiments of the above combination methods, TKI or AAGB is erlotinib or zefitinib, AAGB is a basic compound, AAGB is an anticancer drug, and the monotherapy dose for erlotinib is 150 mg / day , The reduced dose for erlotinib is 100 mg / day; The monotherapy dose for erlotinib is 150 mg / day and the reduced dose for erlotinib is 125 mg / day; The monotherapy dose for erlotinib is 150 mg / day and the reduced dose for erlotinib is 75 mg / day; The monotherapy dose for erlotinib is 150 mg / day and the reduced dose for erlotinib is 50 mg / day; The monotherapy dose for erlotinib is 150 mg / day and the reduced dose for erlotinib is 25 mg / day; The monotherapy dose for erlotinib is 100 mg / day and the reduced dose for erlotinib is 75 mg / day; The monotherapy dose for erlotinib is 100 mg / day and the reduced dose for erlotinib is 50 mg / day; The monotherapy dose for erlotinib is 100 mg / day and the reduced dose for erlotinib is 25 mg / day; The monotherapy dose for zefitinib is 250 mg / day, and the reduced dose for zefitinib is 150 mg / day or 125 mg / day or 100 mg / day; Or about 62 mg / day, or 50 mg / day; The monotherapy dose for gefitinib is 250 mg / day and the reduced dose for gefitinib is 250 mg / day.

In yet another embodiment of the above combination methods, the reduced dose for the anti-ErbB3 antibody is about 1/2 or about 1/4 of the monotherapy dose to the anti-ErbB3 antibody.

The methods described above can be used for the treatment of all cancers that are sensitive to treatment with anti-ErbB3 agents. Non-limiting examples of the types of cancers to be treated include breast, ovary, kidney, lung, prostate, prostatic epithelial tumor, head and neck, brain, spinal cord, liver, bone, skin (eg, melanoma), spleen, testes, bladder, And cancers of the thyroid gland, gastrointestinal system (e.g., colon, rectum, pancreas, gallbladder, stomach, and esophagus with colorectal cancer and oral / pharyngeal cancer), as well as sarcomas, such as clear cell sarcoma or Kaposi's sarcoma.

For all of the above methods, an anti-ErbB3 agent and TKI or AAGB may be administered simultaneously. Optionally, the anti-ErbB3 agent may be administered first followed by TKI or AAGB, or TKI or AAGB may be administered first followed by the anti-ErbB3 agent. Both drugs are administered within a period of time sufficient for the patient to be exposed to the therapeutic efficacy of both agents simultaneously for a period of time. For example, in one embodiment, TKI or AAGB is administered within 1 to 3 weeks after administration of the anti-ErbB3 agent. In another embodiment, the anti-ErbB3 agent is administered within 2 to 3 weeks after administration of TKI or AAGB. In other embodiments of the above methods, the anti-ErbB3 agent represents the first serum half-life, TKI or AAGB represents the second serum half-life, and before administration to the patient of the anti-ErbB3 agent prior to administration of the TKI or AAGB drug Either within 1, 2 or 3 first serum half-lives, or administration of an anti-ErbB3 agent occurs within 1, 2 or 3 second serum half-lives prior to administration of TKI or AAGB.

For all of the above methods given that the patient is a smoker and the patient is given a reduced dose of TKI drug or ErbB3 inhibitor, the reduction is less than the reduced dose of TKI drug or ErbB3 inhibitor given to the same patient if the patient is a non-smoker. Less

In one embodiment, AAGB is a TKI such as erlotinib or zefitinib. In another embodiment, AAGB is a basic drug or neutral lipophilic drug or anticancer agent.

In another aspect, packaged formulations for treating cancer are provided. Packaged formulations contain a drug that is a TKI or AAGB or anti-ErbB3 agent (eg, an anti-ErbB3 inhibitor such as an anti-ErbB3 antibody) formulated for administration to a patient (eg, formulated with a pharmaceutically acceptable carrier). And the packaging further includes a written or printed warning to the healthcare professional or patient as described above. For example, the drug may be a TKI, and a warning may indicate that dose modifications of the TKI should be considered when the TKI is co-administered with an ErbB3 inhibitor; The drug may be an ErbB3 inhibitor, and the warning may indicate that dose modifications of the TKI should be considered when the ErbB3 inhibitor is co-administered with the TKI; Or the drug may be an ErbB3 inhibitor, and the warning may indicate that dose modifications of the ErbB3 inhibitor should be considered when the ErbB3 inhibitor is co-administered with the TKI. Preferably, the dose modification is a dose reduction (compared to the dose used for monotherapy). In other embodiments, the drug may be a TKI and the warning may indicate that the TKI should be administered at a modified dosage when the TKI is co-administered with an ErbB3 inhibitor; The drug may be an ErbB3 inhibitor, and the warning may indicate that the TKI should be administered at a modified dose when the ErbB3 inhibitor is co-administered with the TKI; Or the drug may be an ErbB3 inhibitor, and the warning may indicate that the ErbB3 inhibitor should be administered at a modified dose when the ErbB3 inhibitor is co-administered with the TKI. Preferably, the modified dose is a reduced dose (as compared to the dose used for monotherapy).

In another aspect, packaged formulations for treating cancer are provided. Packaged formulations include a TKI or AAGB or anti-ErbB3 drug (eg, an anti-ErbB3 antibody) in a pharmaceutically acceptable carrier, and the package comprises an anti-ErbB3 agent together with one of the two (TKI or AAGB) described above. Instructions for use according to combination methods (co-administered).

Provided herein are methods of combination therapy for treating cancer in a patient. In these methods, the cancer patient is treated with both an anti-ErbB3 agent and erlotinib or another AAGB. In these combination therapy methods, the dose for erlotinib or other AAGB is reduced compared to the therapeutically effective dose when erlotinib or other AAGB is used alone.

These methods, at least in part, when the anti-ErbB3 agent (eg, anti-ErbB3 antibody) is co-administered with erlotinib, the plasma concentration of erlotinib increases when the concentration of the anti-ErbB3 agent increases. Based on the finding of a point (see Example 1).

Definitions:

The terms "combination therapy", "co-administration" and "co-administered" mean that the first administered therapeutic agent still operates in the patient when the same or second administered therapeutic agent is administered. Administration to a patient of at least two therapeutic agents within a period of time.

The term “monotherapy” refers to administration of a single drug to treat a disease or disorder in the absence of co-administration of other therapeutic agents that are being administered to treat the same disease or disorder.

The terms “therapeutic agent” or “drug” have the ability to reduce or inhibit the severity of symptoms of a disease or disorder, or the frequency and / or duration of asymptomatic or symptom-reduced periods in a disease or disorder. Increases or decreases or prevents impairment or inability due to disease or disorder involvement, inhibits or delays the progression of a disease or disorder, inhibits or delays the development of a disease or disorder, or It is intended to cover any and all compounds having the ability to inhibit or prevent infection. Non-limiting examples of therapeutic agents include small (eg, up to about 700 Daltons) organic molecules, monoclonal antibodies, bispecific antibodies, recombinantly engineered biologics, RNAi compounds, and the like. .

"AAGB" is a drug that exhibits sufficient binding affinity for the human plasma protein alpha 1-acid glycoprotein (AAG) and such binding may alter the bioavailability of the drug in the patient. The term “alpha 1-acid glycoprotein” (also referred to as AAG, AGP or orosomucoid) is intended to encompass all genetic variants of the present plasma protein, including A variants and F1 / S variants. Variants of AAG and drug binding thereto have been described in the art.

TKI is a small molecule (eg, up to about 700 Daltons) tyrosine kinase inhibitor. TKIs are, for example, apatinib, agitinib, bosutinib, canertinib, cediranib, crizotinib, damnacanthal, dasatin Nip (dasatinib), erlotinib, erfitinib, gefitinib, imatinib, lapatinib, lestaurtinib, neratinib, nilotinib, nilotinib, Pazopinib, pelitinib, regorafenib, ruxolitinib, semazanib, sorafenib, sunitinib, toserinib toceranib), tofacitinib, UCN-01, vandetanib, and vatalinib.

The term “anti-ErbB3 agent” refers to any therapeutic agent that binds ErbB3, binds ErbB3-specific ligand or blocks the expression of ErbB3, thereby inhibiting the activity of cellular signaling mediated by ErbB3. . Non-limiting examples of types of anti-ErbB3 agents include antibodies, bispecific antibodies, ligand analogs, ErbB3 or ErbB3 ectodomains, ErbB3 specific RNAi molecules, and similar biologics, as well as certain Tyrosine kinase inhibitors.

The terms "anti-ErbB3 agent" "anti-ErbB3 drug" and "ErbB3 inhibitor" are used interchangeably herein.

The term “antibody” refers to both the entire antibody and the antigen binding fragment (eg “antigen-binding portion”, eg Fabs) or single chains thereof (eg, scFvs) as well as bispecific antibodies and similar engineered variants are included if they maintain the binding specificity of the antibody.

An "anti-ErbB3 antibody" is an antibody that immunospecifically binds to the exogenous domain of ErbB3. Such binding with ErbB3 typically results in K _d below 50 mM (eg, binding affinity corresponding to a K _d value of 50 nM, or higher binding affinity as indicated by lower K _d values), for example As measured by surface plasmon resonance assay or cell binding assay. In one aspect, anti-ErbB3 antibodies inhibit EGF-like ligand-mediated phosphorylation of ErbB3 and / or inhibit ErbB2 / ErbB3 complex formation in living cells. EGF-like ligands include all if each of the following forms: heregulin, EGF, TGFα, betacellulin, heparin-binding epithelial growth factor, biregulin, epigen (epigen), epiregulin, and amphiregulin.

The term “bispecific” as used herein refers to two antigen-binding sites, the first binding site exhibiting immunospecific binding with the first antigen or epitope, and the second antigen or epitope distinct from the first. Refers to a protein comprising a second binding site that exhibits immunospecific binding.

The term “dosage” refers to parameters for administering a drug to a subject in fixed doses per unit time (eg, hourly, daily, weekly, monthly, etc.), which parameters are expressed in units of The size of each dose and the separate doses of each dose, which may be administered orally at a time or injected as a single bolus; or continuously; eg, as an intravenous infusion over a period of time or hours. Frequency of administration.

The term “dose” refers to the amount of drug given in a single administration.

The term "therapeutically effective dose" refers to a dose that has been identified to successfully achieve the desired therapeutic result or effect. For example, a therapeutically effective dose may be a dose recommended for use of the agent in monotherapy (administration of the agent alone, not in combination with one or more additional agents) to achieve the desired therapeutic result or effect.

The term “reduced dosage” means that one or more parameters of the dose have been reduced (eg, compared to a therapeutically effective dose for monotherapy) (eg, at least one dose) The dose of which has been reduced in size or reduced in frequency.

The terms “treat”, “treating”, and “treatment” refer to the therapeutic or prophylactic measures described herein. Methods of "treatment" prevent, cure, delay, reduce or ameliorate the severity of one or more symptoms of cancer in a subject, for example, inhibit the growth or division of cancer cells, or migrate cancer cells in a subject (primarily). ), Administration of one or more drugs to an individual, eg, an individual with cancer, is used to inhibit metastasis, or metastasis.

The term "recommended" generally means as advised by the manufacturer. Specifically, recommended refers to suggestions included by either dose teachings and dose frequency guidelines and prescription information for the drug in question.

Additional aspects of the foregoing and various additional aspects of the disclosure are described in more detail in the following subsections, which should not be considered as limiting.

Along with many other drugs, certain TKIs are known to bind to plasma alpha 1-acid glycoprotein (AAG). Such binding reduces drug bioavailability by reducing the amount of free drug in the blood that can react (eg, enter) with the cells. All TKIs for clinical use (eg, erlotinib, dasatinib, afatinib, zefitinib, imatinib, pazofinib, lapatinib, sunitinib, nilotinib, and sorafenib) exhibit high plasma protein binding , At least erlotinib, lapatinib, imatinib, and zefitinib have been reported to be able to exhibit significant binding with AAGs that can alter their bioavailability and are therefore AAGBs.

I. Combination Therapy

The ability of anti-ErbB3 agents to alter the pharmacokinetics of co-administered AAGB or TKI can be assessed by measuring serum drug levels and calculating pharmacodynamic parameters. The pharmacodynamic parameters referred to herein (eg, Example 1) describe the in vivo characteristics of the drug over time. These include plasma concentrations (C), as well as C _max , T _max , and AUC. The term “C _max ” refers to the measured plasma concentration of the active agent at the maximum point, or peak, followed by the concentration. The term "T _max " refers to the time from drug administration until the C _max is reached. The term "AUC" refers to the area under the curve of the graph of measured plasma concentrations of the active agent against time measured from one time zone to another. For example, AUC _{0- t} is the area under the curve of plasma concentration versus time from time 0 to time t, and time 0 is the time of initial administration of the drug. Time t is the last time zone with measurable plasma concentrations for the individual medications.

If the administration of an anti-ErbB3 agent alters the AUG of co-administered AAGB or TKI, the dose of AAGB in the methods described is reduced compared to the dose to be used when AAGB is administered without co-administration of the anti-ErbB3 agent. do. Thus, in one aspect, as a method of combination therapy for the treatment of cancer patients with anti-ErbB3 agents and drugs that bind alpha 1-acid glycoprotein (AAG),

a) administering an anti-ErbB3 agent;

b) determining a monotherapy dosage for the administration of AAGB;

c) determining a co-administration dose for administration of AAGB when co-administered with an anti-ErbB3 agent, wherein the co-administration dose is a reduced dose compared to a monotherapy dose; And

d) co-administering an anti-ErbB3 agent and AAGB to a cancer patient with AAGB administered according to a co-administration dose.

In one embodiment, the co-administered dose comprises reducing the dose of AAGB. In other words, the reduction includes reducing the size of at least one of the capacities of AAGB. In various embodiments, the dose is 10-75%, 20-60%, or 10 compared to the dose regimen to be administered when AAGB is administered in the absence of co-administration of the anti-ErbB3 agent (eg, as monotherapy). To 50%.

In another embodiment, the reduced dose comprises reducing the frequency of administration. In other words, the reduction includes reducing the number of doses administered per unit time (eg, per day, every other day, per week). Non-limiting examples of reducing the frequency of dosing for combination therapy include administering the formulation every other day or every three days as compared to daily monotherapy, or one daily as compared to two or three daily monotherapy administrations. Administering the formulation once, or administering the formulation once weekly as compared to twice weekly monotherapy administration.

In yet another embodiment, the reduced dose comprises reducing both the dose and the frequency of administration. In other words, the reduction may include reducing the size of the dose and the number of doses administered per unit time.

In yet another embodiment, the time of co-administration of the two agents is determined based on the serum half-lives of the two agents. For example, in one embodiment, the anti-ErbB3 agent represents the first serum half-life, AAGB represents the second serum half-life, and 1 to 3 before administration to the patient of the anti-ErbB3 agent is administered AAGB. Either within the first serum half-lives, or administration of the anti-ErbB3 agent occurs within the second serum half-lives one to three times after administration of AAGB.

Regarding the time frame of co-administration of anti-ErbB3 agent and AAGB, the key factor is that the in vivo activity of the anti-ErbB3 agent (eg, plasma concentration) is still sufficiently high and this affects the pharmacodynamics of co-administered AAGB. The dose of one or both agents is adjusted downward to compensate for this effect on the pharmacodynamics of AAGB.

Example 1 provides non-limiting representative doses for the anti-ErbB3 formulation (anti-ErbB3 antibody) of 6 mg / kg and 12 mg / kg administered intramuscularly once weekly. Thus, in one embodiment, the monotherapy dose is 12 mg / kg / week and the reduced dose is 1/2 or 1/4 of the monotherapy dose, eg, the reduced dose is 6 mg / kg / Week or 3 mg / kg / week; In another aspect, the monotherapy dose is 6 mg / kg / week and the reduced dose is 1/2 or 1/4 of the monotherapy dose, eg, the reduced dose is 3 mg / kg / week or 1.5 mg. / kg / week. In another aspect, the monotherapy dose is 12 mg / kg / week or 6 mg / kg / week and the reduced dose is 1/2 or 1/4 of the monotherapy dose, eg the reduced dose is 12 mg. The / kg / 2 week or 6 mg / kg / 2 week or reduced dose is 12 mg / kg / 4 week or 6 mg / kg / 4 week. Examples 2, 3, and 4 provide representative combination dose therapies for anti-ErbB3 antibodies in combination with TKI or AAGB, such as erlotinib or zefitinib. In one embodiment, the anti-ErbB3 antibody is used in a monotherapy dose and the dose for TKI or AAGB is reduced from its monotherapy dose. For example, a monotherapy dose of 150 mg / day erlotinib is reduced to 100 mg / day when used in combination with an anti-ErbB3 antibody, or a monotherapy dose of 250 mg / day zefitinib is When used in combination with an ErbB3 antibody it is reduced to 125 mg / day, or a monotherapy dose of 250 mg / day of gefitinib is reduced to 250 mg / 48 hours when used in combination with an anti-ErbB3 antibody. In another embodiment, the recommended monotherapy dose of TKI is maintained in combination dose therapy, such as 150 mg / day for erlotinib or 250 mg / day for zefitinib, and the dose of anti-ErbB3 antibody is Reduced from its monotherapy dose. For example, monotherapy doses of anti-ErbB3 antibodies can be, for example, up to 10-75%, for example 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70% or 75 Up to% compared to the monotherapy dose, for example when the monotherapy dose of anti-ErbB3 antibody is 12 mg / kg / day, the reduced dose is about 11 mg / kg / day, about 9.5 mg / day kg / day, 9 mg / kg / day, about 8.5 mg / kg / day, about 7 mg / kg / day, 6 mg / kg / day, about 5 mg / kg / day, about 3.5 mg / kg / day or May be 3 mg / kg / day.

Other suitable reduced doses are the instructions provided herein and drugs combining monotherapy doses for anti-ErbB3 agents (eg, anti-ErbB3 antibodies) and AAG (eg, erlotinib or zefitinib). Will be readily apparent to those skilled in the art based on monotherapy dosages for the patient.

In certain embodiments, further dose adjustments are made if the patient is a smoker. Specifically, a higher TKI dosage than the dose to be selected for use in combination therapy with an anti-ErbB3 agent for patients who are non-smokers is selected for use in combination therapy with a smoker in the anti-ErbB3 agent. For example, a 50 mg / day dose of erlotinib for use in combination therapy with a non-smoker with an anti-ErbB3 agent increased to 75 or 100 or 125 or 150 mg / kg, for example in patients smoking cigarettes. Will be. In another embodiment, a patient who is a smoker receiving a combination therapy of a TKI and an anti-ErbB3 agent has a higher (eg, about 25%, about 50%, about) anti-ErbB3 agent than would be given to a non-smoker patient 75% or about 100% higher). In one embodiment, the monotherapy dose of the anti-ErbB3 agent is for a patient who is a smoker if the patient would receive a lower dose of the anti-ErbB3 agent than the monotherapy dose as otherwise taught in the specification. Used in combination therapy.

Ⅱ. term- ErbB3  Formulations

In the combination therapy methods described herein, the anti-ErbB3 agent is administered to the patient. Preferred anti-ErbB3 agents are anti-ErbB3 antibodies, including monoclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, and combination antibodies, as well as antigen-binding fragments thereof.

In a preferred embodiment, the anti-ErbB3 antibody comprises MM-121, a human anti-ErbB3 antibody currently undergoing Phase II clinical trials. MM-121 and related human anti-ErbB3 antibodies are described in detail in US Pat. No. 7,846,440, US Patent Publications US 20090291085, US 20100056761 and US 20100266584, and International Patent Application PCT Publication No. WO 2008/100624. Are described. In one embodiment, the antibody comprises VH and / or VL regions comprising the amino acid sequences disclosed in SEQ ID NOs: 1 and 2, respectively. In another embodiment, the antibody has CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 3 (CDRH1), SEQ ID NO: 4 (CDRH2), and SEQ ID NO: 5 (CDRH3), and / or SEQ ID NO: 6 CDRL1, CDRL2, and CDRL3 sequences, including amino acid sequences disclosed in (CDRL1), SEQ ID NO: 7 (CDRL2) and SEQ ID NO: 8 (CDRL3). In another embodiment, the antibody comprises a heavy and light chain comprising the amino acid sequences disclosed in SEQ ID NOs: 9 and 10, respectively.

In another embodiment, the antibody comprises VH and / or VL regions comprising the amino acid sequences set forth in SEQ ID NOs: 11 and 12, respectively. In another embodiment, the antibody comprises VH and / or VL regions comprising the amino acid sequences set forth in SEQ ID NOs: 19 and 20, respectively. In another embodiment, the antibody comprises VH and / or VL regions comprising the amino acid sequences set forth in SEQ ID NOs: 27 and 28, respectively. In another embodiment, the antibody comprises VH and / or VL regions comprising the amino acid sequences set forth in SEQ ID NOs: 35 and 36, respectively.

Other examples of anti-ErbB3 antibodies and humanization or their human versions are described, for example, in US Patent Publication 20040197332 and produced by hybridoma cell lines DSM ACC 2527 or DSM ACC 2517 (deposited in DSMZ). Both 1B4C3 (catalog # sc-23865, Santa Cruz Biotechnology) and 2D1D12 (U3 Pharmasa AG); AV-203 (SEQ ID NO: 190 (heavy chain) and SEQ ID NO: 206 (light chain) in International Patent Application PCT Publication No. WO 2011/136911), Aveo Pharmaceutical Co., Ltd .; 8B8 (produced by ATCC® Hybridoma # HB-12070 and described in US Pat. No. 5,968,511 and International Patent Application PCT Publication No. WO 1997/035885); Those described in US Pat. No. 7,846,440; Monoclonal antibody Mab 205.10.2 (SEQ ID NO: 8 (heavy chain) and SEQ ID NO: 10 (light chain) from Roche Glicat company in US Patent Publication No. 20110171222); Mouse anti-ErbB3 antibody (Trellis Biosciences) or bispecific anti-ErbB3 / anti-EGFR antibody described in US Patent Publication No. 20100310557 (eg, SEQ ID NO: in International Patent Application PCT Publication No. WO 2010/108127) 14 (heavy chain) and SEQ ID NO: 13 (light chain) from Genentech).

In another embodiment, the anti-ErbB3 antibody is a bispecific antibody (eg, fusion protein) comprising an anti-ErbB3 antibody linked to a second antibody. In one embodiment, the bispecific antibody comprises an anti-ErbB3 antibody linked with an anti-ErbB2 antibody. Preferred examples of such bispecific antibodies are B2B3-1 as described in International Patent Application No. PCT / US2009 / 040259. The antibody components of B2B3-1 are described in US Pat. No. 7,332,580, as well as International Patent Application No. PCT / US2006 / 023479 (published as WO 2007/084181) and International Patent Application No. PCT / US2007 / 024287 (No. Published as WO 2008/140493).

In another preferred embodiment, the anti-ErbB3 antibody is a bispecific antibody comprising an anti-ErbB3 antibody linked with an anti-IGF1R antibody. Such antibodies are also described in co-proceeding International Patent Application No. PCT / US2010 / 052712 (published as WO 2011/047180) and in co-proceeding International Patent Application No. PCT / US2012 / 034244.

In other embodiments, the anti-ErbB3 agent comprises a first antibody that specifically binds ErbB3 and an insulin-like growth factor 2 receptor (IGF2R), an insulin-like growth factor (IGF), a mesenchymal epithelial cell transfer factor receptor ( c-met), hepatocyte growth factor (HGF), epidermal growth factor receptor (EGFR), epithelial growth factor (EGF), herreulin, fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) ), Platelet-derived growth factor (PDGF), vascular epithelial cell growth factor receptor (VEGFR), vascular epithelial cell growth factor (VEGF), tumor necrosis factor receptor (TNFR), tumor necrosis factor alpha (TNF-α), TNF -β, folate receptor (FOLR), folate transferrin receptor (TfR), mesothelin, Fc receptor, c-kit receptor, c-kit, α4 integram, P-selectin, sphingosine-1-phosphate receptor-1 (S1PR), hyaluronate receptor, leukocyte functional antigen-1 (LFA-1), CD4, CD11, CD18, CD20 , CD25, CD27, CD52, CD70, CD80, CD85, CD95 (Fas receptor), CD106 (vascular adhesion molecule 1 (VCAM1), CD166 (activated leukocyte adhesion molecule (ALCAM)), CD178 (Fas ligand), CD253 (TNF-associated apoptosis-inducing ligand (TRAIL)), ICOS ligand, CCR2, CXCR3, CCR5, CXCL12 (stromal-derived factor 1 (SDF-1)), interleukin 1 (IL-1), CTLA-4 , Receptors alpha and beta, MART-1, gp100, MAGE-1, Eph receptor, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), cancer embryo antigen (CEA), Lewis ^Y , MUC- 1, a second antibody that specifically binds to a protein selected from the group consisting of epithelial cell adhesion molecule (EpCAM), cancer antigen 125 (CA125), prostate specific membrane antigen (PSMA), TAG-72 antigen and fragments thereof Is a bispecific antibody.

Various bispecific antibodies, including the first antibody that specifically binds ErbB3 and the second antibody that specifically binds another protein, are disclosed in International Patent Applications WO 2005/117973 and WO 2006/091209; US Patent No. 8,124,085 and US Patent Publication 20090246206 are described in detail. A variety of bispecific antibodies, including a first antibody that specifically binds ErbB3 and a second antibody that specifically binds another protein, wherein the two antibodies are linked by a modified human serum albumin linker. It is described in detail in patent application 20110059076 and international patent application WO 2009/126920 and WO 2010/059315.

In yet another embodiment, the anti-ErbB3 agent may comprise two or more anti-ErbB3 antibodies, each of which binds to a different epitope on ErbB3. Preferably, the anti-ErbB3 agent may comprise two or three or more different anti-ErbB3 antibodies, each of which binds to a different epitope on ErbB3.

In yet another embodiment, the anti-ErbB3 agent comprises a soluble ErbB3 receptor, or a soluble ErbB2 / ErbB3 receptor complex, capable of binding an ErbB3 ligand (eg, heregulin). Naturally-animal, soluble secreted forms of ErbB3 have been described (p85-soluble ErbB3 or sErbB3). Other soluble forms of ErbB3 are likewise described, see US Pat. No. 7,884,194, which can be prepared by standard recombinant DNA engineering methods through transmembrane of ErbB3 and removal of intracellular domains. In one embodiment, the anti-ErbB3 agent in soluble form of ErbB3 comprises a fusion protein, such as an immunoglobulin (Ig) fusion, wherein the Ig constant domains are linked to the C-terminal end of the soluble form of ErbB3 (ErbB3- Ig fusion protein). The structure and preparation of such Ig fusion proteins are well known in the art (see, eg, US Pat. No. 5,116.).

Ⅲ. AAG Combined with Therapeutic  Formulation

In one embodiment of the combination therapy methods described, a therapeutic agent that binds to alpha 1-acid glycoprotein (AAG) is administered to a patient. AAG is a plasma protein known to be one of the major determinants that bind to a wide variety of drugs and affect drug action, distribution and efficacy. Typically, drugs that can bind AAG are basic compounds. Thus, in one embodiment AAGB is a basic compound.

In another embodiment, AAGB is a protein kinase inhibitor. One protein kinase inhibitor that binds to AAG is erlotinib. Other protein tyrosine kinase inhibitors known to bind AAG include imatinib. In another embodiment, AAGB is an anticancer agent. In one embodiment, the anticancer agent is erlotinib. Non-limiting examples of other anticancer agents known to bind AAG include erlotinib, lapatinib, imatinib, zefitinib, nap-paclitaxel and docetaxel.

Non-limiting examples of other drugs that have been described as binding to AAG include chloropromazine, haloperidol, risperidone, remoxipriride, thiolidazine, and carbamase. Antipsychotic agents such as carbamazepine; Imipramine, nortriptyline, desipramine, clomipramine, desmethylclomipramine, trimipramine, and amipramine Tricyclic antidepressants such as amitriptyline; Beta blockers such as propanolol and oxprenolol; Calcium channel blockers such as verapamil, darodipine, isradipine, nicardipine, and amlodipine; Anti-arrhythmic agents such as propafenone, aprindine, and quinidine; As well as acetaminophen; Capsaicin; Deramciclane; Dicumarol; Dipyradamole; Disopyramide; Disopyramid; Isonazid; Levosemotiadil; Lidocaine (lignocaine); Maprotiline; Methadone; Mifepristone; Phenobarbital; Phenytoin; Progesterone; Pyrazinamide; Rifampicin; Semotiadil; Theophylline; Valproic acid; Vancomycin; And zimelagatran.

In addition, many antiviral agents, such as anti-retroviral agents, are known to be AAGBs, which include, for example, ritonavir, indinavir, saquinavir, nelfinavir, Anti-HIV protease inhibitors including darunavir, and amprenavir, see, eg, US Pat. No. 5,750,493.

The ability of a drug to bind AAG can be determined by any method known in the art, including conventional methods such as equilibrium dialysis and ultrafiltration.

IV. Cancer treatment

The combination therapy methods described herein are useful for the treatment of cancer. The methods can be used for the treatment of all (tumors that express or overexpress ErbB3) if the type of cancer is essential for which ErbB3 would be beneficial. Non-limiting examples of the types of cancers to be treated include breast cancer, ovarian cancer, kidney cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal cancer, lung cancer, prostate cancer, prostate epithelial tumor, sarcoma, melanoma, head and neck cancer, pancreatic cancer, Gallbladder cancer, bladder cancer, brain and / or spinal cord cancers, gastric cancer, liver cancer, bone cancer, skin cancer, spleen cancer, testicular cancer, thyroid cancer, gastric cancer, and oral / pharyngeal cancer.

In one embodiment, the cancer is breast cancer. Examples of types of breast cancers that can be treated include tamoxifen-resistant, estrogen receptor-positive breast cancers, trastuzumab-resistant metastatic breast cancers, hormone-responsive breast cancers and triple negative breast cancers. In another preferred embodiment, the cancer is colon cancer. In another preferred embodiment, the cancer is pancreatic cancer. In another preferred embodiment, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC) or gefitinib-resistant lung cancer. In another preferred embodiment, the cancer is edema, preferably Ewing's sarcoma. In another embodiment, the cancer is bladder cancer. In another embodiment, the cancer is solid cancer. In another embodiment, the cancer is a non-solid cancer such as clear cell sarcoma. In certain aspects, the cancer is ErbB2 and ErbB3 positive tumors (eg, breast tumors and non-small cell lung cancer tumors).

Drugs for combination therapy can be administered to a patient in any suitable form. Typically, the drug is provided in the form of a pharmaceutical composition comprising the drug in a physiologically acceptable carrier.

In another aspect, packaged formulations are provided, such as packaged formulations for treating cancers. Packaged formulations may include, for example, an anti-ErbB3 agent in a pharmaceutically acceptable carrier and instructions for use according to the combination therapy methods described herein. Preferred anti-ErbB3 agents for use in packaged formulations are anti-ErbB3 antibodies, such as those described in subsection II above. In another embodiment, the packaged formulation may include instructions for use according to, for example, AAGB (eg, erlotinib) in a pharmaceutically acceptable carrier and the combination therapy methods described herein. have.

Ⅴ. Logged or Printed Warning

In another aspect, provided are methods and packaged formulations that reduce the risk of deleterious drug-drug interactions (DDIs) between an anti-ErbB3 agent and TKI or AAGB, wherein the method or formulation is an anti-ErbB3 Includes a written or printed warning to the healthcare professional regarding the formulation and / or doses for TKI or AAGB. For example, in various embodiments, as a method of reducing the risk of harmful DDI,

Providing a drug distributor with a tyrosine kinase inhibitor (TKI), the TKI

a) TKI formulated for administration to a patient, and

b) Recorded or printed warnings to medical professionals:

Supplied in a container, wherein the warning indicates that a dose reduction of the TKI should be considered when the TKI is co-administered with the ErbB3 inhibitor;

Supplying the ErbB3 inhibitor to the drug distributor, wherein the ErbB3 inhibitor

a) an ErbB3 inhibitor formulated for administration to a patient, and

b) Recorded or printed warnings to medical professionals:

Supplied in a container, wherein the warning indicates that the dose reduction of TKI should be considered when the ErbB3 inhibitor is co-administered with the tyrosine kinase inhibitor (TKI), or the warning indicates that the ErbB3 inhibitor should Indicating that a dose reduction of ErbB3 inhibitor should be considered when co-administered to a patient together;

Supplying the drug distributor a drug that is an alpha 1-acid glycoprotein binder (AAGB), wherein AAGB

a) AAGB formulated for administration to a patient, and

b) Recorded or printed warnings to medical professionals:

Supplied in a container, wherein the warning indicates that a dose reduction of AAGB should be considered when AAGB is co-administered with a ErbB3 inhibitor to the patient;

 Supplying the ErbB3 inhibitor to the drug distributor, wherein the ErbB3 inhibitor

a) an ErbB3 inhibitor formulated for administration to a patient, and

b) Recorded or printed warnings to medical professionals:

Supplied in a container, the warning indicates, or warns, that a dose reduction of AAGB should be considered when the ErbB3 inhibitor is co-administered to a patient with a drug that is an alpha 1-acid glycoprotein binder (AAGB) Provides an indication that a dose reduction of an ErbB3 inhibitor should be considered when co-administered to a patient with a drug whose ErbB3 inhibitor is AAGB.

In another aspect, written or given to a healthcare professional regarding packaged formulations comprising one or more of an anti-ErbB3 agent, TKI and / or AAGB, formulated for administration, and an anti-ErbB3 agent, TKI and / or AAGB, or A printed warning is provided. For example, various embodiments provide such a package comprising a drug in a container,

The drug is a tyrosine kinase inhibitor (TKI) formulated for administration to a patient; The package further includes a written or printed warning to the healthcare professional or patient, the warning indicating that when the TKI is co-administered with the ErbB3 inhibitor to the patient, dose modifications of the TKI should be considered;

The drug is an ErbB3 inhibitor formulated for administration to a patient; The package further includes a written or printed warning to the healthcare professional or patient, and the warning indicates that when the ErbB3 inhibitor is co-administered to the patient with a tyrosine kinase inhibitor (TKI), the dose modification of the TKI should be considered. Instruct;

The drug is an ErbB3 inhibitor formulated for administration to a patient; The package further includes a written or printed warning to the healthcare professional or the patient, the warning indicating that when the ErbB3 inhibitor is co-administered with the tyrosine kinase inhibitor to the patient, a dose variation of the ErbB3 inhibitor should be considered. ;

The drug is a tyrosine kinase inhibitor (TKI) formulated for administration to a patient; The package further includes a written or printed warning to the healthcare professional or patient, the warning indicating that when the TKI is co-administered with the ErbB3 inhibitor, the TKI should be administered at a modified dosage;

The drug is an ErbB3 inhibitor formulated for administration to a patient; The package further includes a written or printed warning to the healthcare professional or patient, wherein the warning indicates that when the ErbB3 inhibitor is co-administered with the tyrosine kinase inhibitor (TKI) to the patient, the TKI should be administered at a modified dosage. To indicate; or

The drug is an ErbB3 inhibitor formulated for administration to a patient; The package further includes a written or printed warning to the healthcare professional or patient, wherein the warning indicates that when the ErbB3 inhibitor is co-administered with the tyrosine kinase inhibitor to the patient, the ErbB3 inhibitor should be administered at a modified dosage. To provide packaging.

With respect to the methods and packaged formulations described above, recorded or printed alerts may include, for example, recorded audio alerts, recorded video alerts, recorded alerts in computer readable form, or printed alerts. . The recorded audio and / or video alert may be a device capable of triggering an audio or visual message comprising the alert. Various devices incorporating the technology to provide such recorded audio or visual alerts are particularly suitable for providing alerts on smartphones, iPods, or other digital audio / video players, as well as for example when opening containers. Available in the art, such as those described in 7,802,386. Computer readable forms that include warnings include, for example, magnetic tape, Blu-ray discs, minidisks, DVDs, CD-ROMs, external hard drives, flash drives (eg, USB flash drives), or various types listed in Table 1 below. All memory cards may be the same memory card. Table 1 shows the memory cards.

VI. Examples

The following examples are illustrative and non-limiting.

Example  1: anti- ErbB3  Antibodies and Erlotinib  Pharmacodynamics of Combination Therapy

In this example, human cancer patients were treated with a combination of anti-ErbB3 monoclonal antibody, MM-121, and erlotinib, a protein kinase inhibitor, and various pharmacodynamic parameters were measured. Patients were awarded one of two different doses of MM-121 antibody administered intramuscularly each week (either 6 mg / kg or 12 mg / kg). Patients were also awarded one of two different doses of erlotinib (either 100 mg or 150 mg) administered daily orally. Antibody administration began on day 1 and continued at weekly doses, erlotinib administration started on day 2 and continued on daily doses. Pharmacodynamic parameters were monitored for the duration of treatment until the patient's cancer progressed or the patient left the study. Each patient received at least two doses of the MM-121 antibody.

The following pharmacodynamic parameters were measured for the antibody: T _max (estimated time after administration of antibody to reach maximum concentration in plasma), C _max (maximum concentration of antibody in plasma observed after administration) and AUC ( Area under the plasma concentration time curve as an estimate of bioavailability). For erlotinib, average plasma concentrations were measured. The results are summarized in Table 2 below. Table 2 shows the pharmacokinetics of MM-121 and erlotinib coadministration.

The results show that patients treated with 12 mg / kg of anti-ErbB3 antibody exhibit approximately 2 to 3 times higher mean plasma concentrations of erlotinib compared to patients treated with only 6 mg / kg of anti-ErbB3 antibody. Showed that For example, patients 2 and 5 were treated with 150 mg erlotinib, respectively, but with 6 mg / kg or 12 mg / kg MM-121, respectively, and the mean plasma concentration of erlotinib was better than patient 2 It was approximately 2.19 times higher at five times. Similarly, patients 1 and 8 were treated with 100 mg erlotinib, respectively, but with 6 mg / kg or 12 mg / kg MM-121, respectively, and the mean plasma concentration of erlotinib was better than patient 1 About 2.02 times higher in burns.

In view of the above, these results indicate that ErbB3 antagonism in patients may affect the pharmacodynamics of peer therapy, TKI or AAGB, which is co-administered with combination therapy with anti-ErbB3 agents. Specifically, the results indicate that mean plasma concentrations of co-administered TKI and AAGB drugs such as erlotinib or zefitinib increase with increasing amount of ErbB3 antagonism.

Example  2: anti- ErbB3  Antibodies and Erlotinib  or Gefitinib  Combination Dose Therapies for

Cancer patients in need of treatment with anti-ErbB3 antibodies and erlotinib or zefitinib are selected for treatment. Monotherapy dosages for the treatment of erlotinib are, for example, 150 mg / day. Monotherapy dosages for gefitinib treatment are, for example, 250 mg / day. For combination therapy, for erlotinib (as compared to the monotherapy dose of erlotinib at 150 mg / day) or for gefitinib (compare with monotherapy dose of zefitinib at 250 mg / day Reduced dose is determined by the antibody (eg, MM-121 or AMG888) with a monotherapy dose. Thus, a combined dose regimen for the treatment of cancer patients consisting of administration of a monotherapy dose of MM-121 or a monotherapy dose of AMG888 (independently) was 100 mg / day of erlotinib (erlotinib). Reduced dose compared to monotherapy dose for) or 125 mg / day of gefitinib (reduced dose compared to monotherapy dose for zefitinib) or 250 mg / kg / 48 hours Reduced dose compared to monotherapy dose for phytinib).

Example  3: anti- ErbB3  Antibodies and Zetitnib  or Erlotinib  Combination Dose Therapies for

Cancer patients in need of treatment with anti-ErbB3 antibodies and tyrosine kinase inhibitors (TKI) zephytinib or TKI erlotinib are selected for treatment. MM-121 or AMG888 is administered in a monotherapy dose. Monotherapy dosages for gefitinib treatment are, for example, 250 mg / day. Monotherapy dosages for the treatment of erlotinib are, for example, 150 mg / day. For combination therapy, a reduced dose of anti-ErbB3 antibody MM-121 or a reduced dose of anti-ErbB3 antibody AMG888 is co-administered with a monotherapy dose of zefitinib or a monotherapy dose of erlotinib. To be selected. Accordingly, the combined dose regimen for the treatment of cancer patients is: (independently) half of the monotherapy dose of MM-121 with 250 mg / day zefitinib or 150 mg / day erlotinib or Half of the monotherapy dose of AMG888.

Example  4: anti- ErbB3  Antibodies and Zetitnib  or Erlotinib  Combination Dose Therapies for

Cancer patients in need of treatment with anti-ErbB3 antibodies and tyrosine kinase inhibitors (TKI) erlotinib or TKI zefitinib are selected for treatment. Anti-ErbB3 antibodies with heavy chain amino acid sequences disclosed in SEQ ID NO: 70 of US Pat. No. 7,705,130 and light chain amino acid sequences set forth in SEQ ID NO: 72 of US Pat. No. 7,705,130 were selected for use as anti-ErbB3 antibodies. Anti-ErbB3 antibodies are administered to patients in monotherapy doses by intravenous infusion once every three weeks at a concentration of 70 mg / mL. The monotherapy dose for the treatment of erlotinib is 150 mg / day. The monotherapy dosage for gefitinib treatment is 250 mg / day. At the monotherapy dose of anti-ErbB3 antibody, a reduced dose regimen for erlotinib or a reduced dose regimen for zefitinib is selected (compared to the monotherapy dose) and administered to the patient.

Example  5: for combination therapy Tyrosine Kinase  Packaging and Distribution of Inhibitors

Tyrosine kinase inhibitors (TKIs) (e.g., erlotinib or zefitinib) are formulated for administration to a patient, placed in a container and then packaged in a package, where the package is recorded for a medical professional (e.g., a physician) Also included are alerts such as audio alerts, recorded video alerts, recorded alerts in computer readable form, or printed alerts. This warning indicates that when a TKI is co-administered with a ErbB3 inhibitor (eg, an anti-ErbB3 antibody) to a patient, dose modifications of the TKI, such as a dose reduction of the TKI, should be considered. The warning also indicates that a dose reduction is suggested, for example, in 25 mg or 50 mg or about 62 mg or 125 mg increments per dose of TKI. Packages containing the TKI formulations in the container and a warning for the medical professional are supplied to the drug distributor.

Example  6: anti- for combination therapy ErbB3  Packaging and Distribution of Antibodies

An anti-ErbB3 antibody, such as MM-121 or AMG888, is formulated for administration to a patient and placed in a container and then packaged in a package, where the package is recorded with an audio alert, recorded for a medical professional (eg, a physician) Alerts such as video alerts, computer recorded alerts, or printed alerts are also included. This warning should be taken into account when dose modifications of TKI, such as dose reduction of TKI, are taken into account when an anti-ErbB3 antibody is co-administered to a patient with a tyrosine kinase inhibitor (TKI) (eg, erlotinib or zefitinib). Point out what to do. The warning optionally also indicates that a dose reduction is suggested, for example, in 25 mg or 50 mg or about 62 mg or 125 mg increments per dose of TKI. A package containing the anti-ErbB3 antibody formulations in a container and a warning for a medical professional is supplied to the drug distributor.

Summary of sequences

VII . Integration by Reference

US, international, or other patents or patent applications or publications referred to herein are hereby incorporated by reference in their entirety.

                               SEQUENCE LISTING <110> MERRIMACK PHARMACEUTICALS, INC.   <120> METHODS FOR PREVENTING TOXIC DRUG-DRUG INTERACTIONS IN       COMBINATION THERAPIES COMPRISING ANTI-ERBB3 AGENTS <130> MMJ-029 <140> <141> <150> PCT / US2012 / 036619 <151> 2012-05-04 <150> 61 / 483,195 <151> 2011-05-06 <160> 43 <170> PatentIn version 3.5 <210> 1 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       polypeptide <400> 1 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr             20 25 30 Val Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Ser Ile Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Thr Arg Gly Leu Lys Met Ala Thr Ile Phe Asp Tyr Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 2 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       polypeptide <400> 2 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr             20 25 30 Asn Val Val Ser Trp Gln Gln His Pro Gly Lys Ala Pro Lys Leu         35 40 45 Ile Ile Tyr Glu Val Ser Gln Arg Pro Ser Gly Val Ser Asn Arg Phe     50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser                 85 90 95 Ser Ile Phe Val Ile Phe Gly Gly Gly Thr Lys Val Thr Val Leu             100 105 110 <210> 3 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 3 His Tyr Val Met Ala 1 5 <210> 4 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 4 Ser Ile Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 5 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 5 Gly Leu Lys Met Ala Thr Ile Phe Asp Tyr 1 5 10 <210> 6 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 6 Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr Asn Val Val Ser 1 5 10 <210> 7 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 7 Glu Val Ser Gln Arg Pro Ser 1 5 <210> 8 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 8 Cys Ser Tyr Ala Gly Ser Ser Ile Phe Val Ile 1 5 10 <210> 9 <211> 445 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       polypeptide <400> 9 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr             20 25 30 Val Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Ser Ile Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Thr Arg Gly Leu Lys Met Ala Thr Ile Phe Asp Tyr Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe         115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu     130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu                 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser             180 185 190 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro         195 200 205 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu     210 215 220 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu                 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln             260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys         275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu     290 295 300 Thr Val Val His Glu Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys                 325 330 335 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser             340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys         355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln     370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln                 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn             420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys         435 440 445 <210> 10 <211> 217 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       polypeptide <400> 10 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr             20 25 30 Asn Val Val Ser Trp Gln Gln His Pro Gly Lys Ala Pro Lys Leu         35 40 45 Ile Ile Tyr Glu Val Ser Gln Arg Pro Ser Gly Val Ser Asn Arg Phe     50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser                 85 90 95 Ser Ile Phe Val Ile Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly             100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu         115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Val Ser Asp Phe     130 135 140 Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val 145 150 155 160 Lys Val Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys                 165 170 175 Tyr Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser             180 185 190 His Arg Ser Tyr Ser Cys Arg Val Thr His Glu Gly Ser Thr Val Glu         195 200 205 Lys Thr Val Ala Pro Ala Glu Cys Ser     210 215 <210> 11 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       polypeptide <400> 11 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr             20 25 30 Asn Met Arg Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Val Ile Tyr Pro Ser Gly Gly Ala Thr Arg Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Gly Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr             100 105 110 Leu Val Thr Val Ser Ser         115 <210> 12 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       polypeptide <400> 12 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Asp Ser Asn Ile Gly Arg Asn             20 25 30 Tyr Ile Tyr Trp Tyr Gln Gln Phe Pro Gly Thr Ala Pro Lys Leu Leu         35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Ile Ser     50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Glu Tyr His Cys Gly Thr Trp Asp Asp Ser Leu                 85 90 95 Ser Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu             100 105 110 <210> 13 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 13 Ala Tyr Asn Met Arg 1 5 <210> 14 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 14 Val Ile Tyr Pro Ser Gly Gly Ala Thr Arg Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 15 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 15 Gly Tyr Tyr Tyr Tyr Gly Met Asp Val 1 5 <210> 16 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 16 Ser Gly Ser Asp Ser Asn Ile Gly Arg Asn Tyr Ile Tyr 1 5 10 <210> 17 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 17 Arg Asn Asn Gln Arg Pro Ser 1 5 <210> 18 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 18 Gly Thr Trp Asp Asp Ser Leu Ser Gly Pro Val 1 5 10 <210> 19 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       polypeptide <400> 19 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr             20 25 30 Gly Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Tyr Ile Ser Pro Ser Gly Gly His Thr Lys Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Lys Val Leu Glu Thr Gly Leu Leu Val Asp Ala Phe Asp Ile Trp             100 105 110 Gly Gln Gly Thr Met Val Thr Val Ser Ser         115 120 <210> 20 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       polypeptide <400> 20 Gln Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Tyr Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys Ser Gly Asp Gln Leu Gly Ser Lys Phe Val             20 25 30 Ser Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Val Leu Val Met Tyr         35 40 45 Lys Asp Lys Arg Arg Pro Ser Glu Ile Pro Glu Arg Phe Ser Gly Ser     50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Ile 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Ser Ser Thr Tyr Val                 85 90 95 Phe Gly Thr Gly Thr Lys Val Thr Val Leu             100 105 <210> 21 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 21 Ala Tyr Gly Met Gly 1 5 <210> 22 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 22 Tyr Ile Ser Pro Ser Gly Gly His Thr Lys Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 23 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 23 Val Leu Glu Thr Gly Leu Leu Val Asp Ala Phe Asp Ile 1 5 10 <210> 24 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 24 Ser Gly Asp Gln Leu Gly Ser Lys Phe Val Ser 1 5 10 <210> 25 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 25 Tyr Lys Asp Lys Arg Arg Pro Ser 1 5 <210> 26 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 26 Gln Ala Trp Asp Ser Ser Thr Tyr Val 1 5 <210> 27 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       polypeptide <400> 27 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Trp Tyr             20 25 30 Gly Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Tyr Ile Ser Pro Ser Gly Gly Ile Thr Val Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Leu Asn Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gln Gly Thr             100 105 110 Thr Val Thr Val Ser Ser         115 <210> 28 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       polypeptide <400> 28 Gln Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Ser Ser Ser Ser Val 1 5 10 15 Gly Asp Arg Ile Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Gly Asp             20 25 30 Ser Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Arg Leu Leu         35 40 45 Ile Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Pro Arg Phe Ser     50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Phe Arg Ser Leu Gln 65 70 75 80 Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Ser Ala Asn Ala Pro                 85 90 95 Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys             100 105 <210> 29 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 29 Trp Tyr Gly Met Gly 1 5 <210> 30 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 30 Tyr Ile Ser Pro Ser Gly Gly Ile Thr Val Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 31 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 31 Leu Asn Tyr Tyr Tyr Gly Leu Asp Val 1 5 <210> 32 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 32 Gln Ala Ser Gln Asp Ile Gly Asp Ser Leu Asn 1 5 10 <210> 33 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 33 Asp Ala Ser Asn Leu Glu Thr 1 5 <210> 34 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 34 Gln Gln Ser Ala Asn Ala Pro Phe Thr 1 5 <210> 35 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       polypeptide <400> 35 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr             20 25 30 Gly Met Trp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Tyr Ile Gly Ser Ser Gly Gly Pro Thr Tyr Tyr Val Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Gly Gly Arg Gly Thr Pro Tyr Tyr Phe Asp Ser Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 36 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       polypeptide <400> 36 Gln Tyr Glu Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg Trp             20 25 30 Asn Ile Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu         35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe     50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser                 85 90 95 Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu             100 105 110 <210> 37 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 37 Arg Tyr Gly Met Trp 1 5 <210> 38 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 38 Tyr Ile Gly Ser Ser Gly Gly Pro Thr Tyr Tyr Val Asp Ser Val Lys 1 5 10 15 Gly      <210> 39 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 39 Gly Arg Gly Thr Pro Tyr Tyr Phe Asp Ser 1 5 10 <210> 40 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 40 Thr Gly Thr Ser Ser Asp Ile Gly Arg Trp Asn Ile Val Ser 1 5 10 <210> 41 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 41 Asp Val Ser Asn Arg Pro Ser 1 5 <210> 42 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic       peptide <400> 42 Ser Ser Tyr Thr Ser Ser Ser Thr Trp Val 1 5 10 <210> 43 <211> 1323 <212> PRT <213> Homo sapiens <400> 43 Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr Leu Asn Gly 1 5 10 15 Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr Leu Tyr Lys             20 25 30 Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu Ile Val Leu         35 40 45 Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile Arg Glu Val     50 55 60 Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr Leu Pro Leu 65 70 75 80 Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp Gly Lys Phe                 85 90 95 Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser His Ala Leu             100 105 110 Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser Gly Gly Val         115 120 125 Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr Ile Asp Trp     130 135 140 Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val Lys Asp Asn 145 150 155 160 Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly Arg Cys Trp                 165 170 175 Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr Ile Cys Ala             180 185 190 Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn Gln Cys Cys         195 200 205 His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp Thr Asp Cys     210 215 220 Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val Pro Arg Cys 225 230 235 240 Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu Glu Pro Asn                 245 250 255 Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala Ser Cys Pro             260 265 270 His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala Cys Pro Pro         275 280 285 Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys Glu Pro Cys     290 295 300 Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser Gly Ser Arg 305 310 315 320 Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val Asn Cys Thr                 325 330 335 Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr Gly Leu Asn Gly Asp             340 345 350 Pro Trp His Lys Ile Pro Ala Leu Asp Pro Glu Lys Leu Asn Val Phe         355 360 365 Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln Ser Trp Pro     370 375 380 Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr Thr Ile Gly 385 390 395 400 Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile Met Lys Asn                 405 410 415 Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu Ile Ser Ala             420 425 430 Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr His His Ser         435 440 445 Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu Arg Leu Asp     450 455 460 Ile Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu Gly Lys Val 465 470 475 480 Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro Gly Pro Gly                 485 490 495 Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val Cys Val Thr             500 505 510 His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala His Glu Ala         515 520 525 Glu Cys Phe Ser Cys His Pro Glu Cys Gln Pro Met Glu Gly Thr Ala     530 535 540 Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys Ala His Phe 545 550 555 560 Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly Val Leu Gly                 565 570 575 Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln Asn Glu Cys Arg             580 585 590 Pro Cys His Glu Asn Cys Thr Gln Gly Cys Lys Gly Pro Glu Leu Gln         595 600 605 Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr His Leu Thr     610 615 620 Met Ala Leu Thr Val Ile Ala Gly Leu Val Val Ile Phe Met Met Leu 625 630 635 640 Gly Gly Thr Phe Leu Tyr Trp Arg Gly Arg Arg Ile Gln Asn Lys Arg                 645 650 655 Ala Met Arg Arg Tyr Leu Glu Arg Gly Glu Ser Ile Glu Pro Leu Asp             660 665 670 Pro Ser Glu Lys Ala Asn Lys Val Leu Ala Arg Ile Phe Lys Glu Thr         675 680 685 Glu Leu Arg Lys Leu Lys Val Leu Gly Ser Gly Val Phe Gly Thr Val     690 695 700 His Lys Gly Val Trp Ile Pro Glu Gly Glu Ser Ile Lys Ile Pro Val 705 710 715 720 Cys Ile Lys Val Ile Glu Asp Lys Ser Gly Arg Gln Ser Phe Gln Ala                 725 730 735 Val Thr Asp His Met Leu Ala Ile Gly Ser Leu Asp His Ala His Ile             740 745 750 Val Arg Leu Leu Gly Leu Cys Pro Gly Ser Ser Leu Gln Leu Val Thr         755 760 765 Gln Tyr Leu Pro Leu Gly Ser Leu Leu Asp His Val Arg Gln His Arg     770 775 780 Gly Ala Leu Gly Pro Gln Leu Leu Leu Asn Trp Gly Val Gln Ile Ala 785 790 795 800 Lys Gly Met Tyr Tyr Leu Glu Glu His Gly Met Val His Arg Asn Leu                 805 810 815 Ala Ala Arg Asn Val Leu Leu Lys Ser Pro Ser Gln Val Gln Val Ala             820 825 830 Asp Phe Gly Val Ala Asp Leu Leu Pro Pro Asp Asp Lys Gln Leu Leu         835 840 845 Tyr Ser Glu Ala Lys Thr Pro Ile Lys Trp Met Ala Leu Glu Ser Ile     850 855 860 His Phe Gly Lys Tyr Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val 865 870 875 880 Thr Val Trp Glu Leu Met Thr Phe Gly Ala Glu Pro Tyr Ala Gly Leu                 885 890 895 Arg Leu Ala Glu Val Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Ala             900 905 910 Gln Pro Gln Ile Cys Thr Ile Asp Val Tyr Met Val Met Val Lys Cys         915 920 925 Trp Met Ile Asp Glu Asn Ile Arg Pro Thr Phe Lys Glu Leu Ala Asn     930 935 940 Glu Phe Thr Arg Met Ala Arg Asp Pro Pro Arg Tyr Leu Val Ile Lys 945 950 955 960 Arg Glu Ser Gly Pro Gly Ile Ala Pro Gly Pro Glu Pro His Gly Leu                 965 970 975 Thr Asn Lys Lys Leu Glu Glu Val Glu Leu Glu Pro Glu Leu Asp Leu             980 985 990 Asp Leu Asp Leu Glu Ala Glu Glu Asp Asn Leu Ala Thr Thr Thr Leu         995 1000 1005 Gly Ser Ala Leu Ser Leu Pro Val Gly Thr Leu Asn Arg Pro Arg     1010 1015 1020 Gly Ser Gln Ser Leu Leu Ser Pro Ser Ser Gly Tyr Met Pro Met     1025 1030 1035 Asn Gln Gly Asn Leu Gly Glu Ser Cys Gln Glu Ser Ala Val Ser     1040 1045 1050 Gly Ser Ser Glu Arg Cys Pro Arg Pro Val Ser Leu His Pro Met     1055 1060 1065 Pro Arg Gly Cys Leu Ala Ser Glu Ser Ser Glu Gly His Val Thr     1070 1075 1080 Gly Ser Glu Ala Glu Leu Gln Glu Lys Val Ser Met Cys Arg Ser     1085 1090 1095 Arg Ser Arg Ser Arg Ser Pro Arg Pro Arg Gly Asp Ser Ala Tyr     1100 1105 1110 His Ser Gln Arg His Ser Leu Leu Thr Pro Val Thr Pro Leu Ser     1115 1120 1125 Pro Pro Gly Leu Glu Glu Glu Asp Val Asn Gly Tyr Val Met Pro     1130 1135 1140 Asp Thr His Leu Lys Gly Thr Pro Ser Ser Arg Glu Gly Thr Leu     1145 1150 1155 Ser Ser Val Gly Leu Ser Ser Val Leu Gly Thr Glu Glu Glu Asp     1160 1165 1170 Glu Asp Glu Glu Tyr Glu Tyr Met Asn Arg Arg Arg Arg His Ser     1175 1180 1185 Pro Pro His Pro Pro Arg Pro Ser Ser Leu Glu Glu Leu Gly Tyr     1190 1195 1200 Glu Tyr Met Asp Val Gly Ser Asp Leu Ser Ala Ser Leu Gly Ser     1205 1210 1215 Thr Gln Ser Cys Pro Leu His Pro Val Pro Ile Met Pro Thr Ala     1220 1225 1230 Gly Thr Thr Pro Asp Glu Asp Tyr Glu Tyr Met Asn Arg Gln Arg     1235 1240 1245 Asp Gly Gly Gly Pro Gly Gly Asp Tyr Ala Ala Met Gly Ala Cys     1250 1255 1260 Pro Ala Ser Glu Gln Gly Tyr Glu Glu Met Arg Ala Phe Gln Gly     1265 1270 1275 Pro Gly His Gln Ala Pro His Val His Tyr Ala Arg Leu Lys Thr     1280 1285 1290 Leu Arg Ser Leu Glu Ala Thr Asp Ser Ala Phe Asp Asn Pro Asp     1295 1300 1305 Tyr Trp His Ser Arg Leu Phe Pro Lys Ala Asn Ala Gln Arg Thr     1310 1315 1320

Claims (51)

Supplying a tyrosine kinase inhibitor (TKI) to the drug distributor, wherein the TKI is a container containing a) a TKI formulated for administration to the patient, and b) a written or printed warning to the healthcare professional: And, wherein the warning indicates that when a TKI is co-administered with a ErbB3 inhibitor to the patient, a dose reduction of the TKI should be considered. Supplying an ErbB3 inhibitor to the drug distributor, wherein the ErbB3 inhibitor is supplied in a container comprising a) an ErbB3 inhibitor formulated for administration to a patient, and b) a written or printed warning to the healthcare professional: The warning indicates that when the ErbB3 inhibitor is co-administered with a tyrosine kinase inhibitor (TKI) to the patient, a dose reduction of the TKI should be considered, or the warning indicates that the ErbB3 inhibitor is co-administered to the patient with the TKI. When administered, a method of reducing the risk of deleterious drug-drug interactions, indicating that a dose reduction of the ErbB3 inhibitor should be considered. Providing a drug distributor with a drug that is an alpha 1-acid glycoprotein binder (AAGB), the AAGB comprising a) AAGB formulated for administration to a patient, and b) a recorded or printed warning to a healthcare professional Supplied in a container containing: the warning indicates the risk of deleterious drug-drug interactions, indicating that when AAGB is co-administered with an ErbB3 inhibitor to the patient, a dose reduction of AAGB should be considered How to reduce. Supplying an ErbB3 inhibitor to the drug distributor, wherein the ErbB3 inhibitor is supplied in a container comprising a) an ErbB3 inhibitor formulated for administration to a patient, and b) a written or printed warning to the healthcare professional: The warning indicates that when the ErbB3 inhibitor is co-administered to a patient with a drug that is an alpha 1-acid glycoprotein binder (AAGB), the dose reduction of AAGB should be considered, or the warning indicates that the ErbB3 inhibitor should be considered. When co-administered to a patient with a drug that is AAGB, a method of reducing the risk of deleterious drug-drug interactions, indicating that a dose reduction of the ErbB3 inhibitor should be considered. The method according to any one of claims 1 to 4,
Wherein the recorded or printed alert comprises one or more of a recorded audio alert, a recorded video alert, a recorded alert in computer readable form, or a printed alert. 6. The method according to any one of claims 1 to 5,
Wherein said medical professional is a doctor, physician assistant, nurse, or pharmacist. 7. The method according to any one of claims 1 to 6,
Wherein the TKI or AAGB is erlotinib and the warning further indicates that a dose reduction of 25 mg or 50 mg increments is suggested. 7. The method according to any one of claims 1 to 6,
Wherein the TKI or AAGB is zefitinib and the warning further indicates that a dose reduction of 125 mg or about 62 mg increments is suggested. The method according to claim 1 or 3,
Wherein the patient suffers from cancer in which treatment with TKI or AAGB is indicated. The method according to claim 2 or 4,
Wherein the patient suffers from cancer in which treatment with an ErbB3 inhibitor is indicated. The method according to any one of claims 1 to 6 and 10,
Wherein said ErbB3 inhibitor is an anti-ErbB3 antibody. 12. The method of claim 11,
The anti-ErbB3 antibody is an antibody having a heavy chain sequence set forth in SEQ ID NO: 1 and a light chain sequence set forth in SEQ ID NO: 2. A package comprising a drug in a container, the drug being a tyrosine kinase inhibitor (TKI) formulated for administration to a patient; The package further includes a written or printed warning to the healthcare professional or the patient, the warning indicating that when the TKI is co-administered with an ErbB3 inhibitor, dose modifications of the TKI should be considered. , Packing. A package comprising a drug in a container, the drug being an ErbB3 inhibitor formulated for administration to a patient; The package further includes a written or printed warning to the healthcare professional or the patient, wherein the warning should be taken into account when the ErbB3 inhibitor is co-administered with a tyrosine kinase inhibitor (TKI). Directing point, packaging. A package comprising a drug in a container, the drug being an ErbB3 inhibitor formulated for administration to a patient; The package further includes a written or printed warning to the healthcare professional or the patient, wherein the warning indicates that when ErbB3 inhibitors are co-administered with tyrosine kinase inhibitors, dose modifications of the ErbB3 inhibitors should be considered. Directed, package. 16. The method according to any one of claims 13 to 15,
Wherein the dose modification is a dose reduction. A package comprising a drug in a container, the drug being a tyrosine kinase inhibitor (TKI) formulated for administration to a patient; The package further includes a written or printed warning to the healthcare professional or the patient, the warning indicating that the TKI should be administered at a modified dose when the TKI is co-administered with an ErbB3 inhibitor. Done, packaging. A package comprising a drug in a container, the drug being an ErbB3 inhibitor formulated for administration to a patient; The package further includes a written or printed warning to the healthcare professional or the patient, wherein the warning is administered at a modified dosage when the Tb is co-administered with the ErbB3 inhibitor with a tyrosine kinase inhibitor (TKI). Packaging, which dictates the point that should be. A package comprising a drug in a container, the drug being an ErbB3 inhibitor formulated for administration to a patient; The package further includes a written or printed warning to the healthcare professional or the patient, wherein the warning is at an altered dose when the ErbB3 inhibitor is co-administered with the tyrosine kinase inhibitor (TKI). Packaging indicating the point to be administered. 20. The method according to any one of claims 17 to 19,
Wherein the modified dosage is a reduced dosage. As a method of combination therapy, the therapy is for the treatment of patients suffering from cancer, wherein the combination therapy is either an anti-ErbB3 drug and a tyrosine kinase inhibitor (TKI) drug or an alpha 1-acid glycoprotein binding (AAGB) drug. The anti-, wherein both are administered, one or both of 1) the TKI drug or the AAGB drug, and 2) the anti-ErbB3 drug is administered to the patient in one or more modified dosages. Administering both an ErbB3 drug and the TKI drug or the AAGB drug. 22. The method of claim 21,
Wherein each modified dose of drug is a reduced dose as compared to monotherapy dose treatment with the drug in such patients. 23. The method of claim 22,
Wherein the TKI drug or the AAGB drug is administered at a reduced dose and the anti-ErbB3 drug is not administered at a reduced dose. 23. The method of claim 22,
Wherein the ErbB3 drug is administered at a reduced dose and the TKI drug or the AAGB drug is not administered at a reduced dose. 23. The method of claim 22,
Wherein each of the 1) the TKI drug or the AAGB drug and 2) the anti-ErB3 drug is administered at a reduced dosage. The method according to any one of claims 22 to 25,
Wherein the amount of each reduced dose is reduced from 10 to 75%. As a method of combination therapy, the therapy is for the treatment of patients suffering from cancer, wherein the combination therapy is either an anti-ErbB3 drug and a tyrosine kinase inhibitor (TKI) drug or an alpha 1-acid glycoprotein binding (AAGB) drug. The anti-ErbB3 drug, wherein one or both administration is administered, wherein 1) the TKI drug or the AAGB drug, and 2) both or both of the anti-ErbB3 drug are administered to the patient at a modified dose frequency and Administering both the TKI drug or the AAGB drug. 28. The method of claim 27,
Wherein each modified frequency of administration is a reduced frequency compared to the frequency of administration recommended for monotherapy treatment with the drug in such patients. 29. The method of claim 28,
Wherein the TKI drug or the AAGB drug is administered at a reduced frequency and the anti-ErbB3 drug is not administered at a reduced frequency. 29. The method of claim 28,
Wherein the ErbB3 drug is administered at a reduced frequency and the TKI drug or the AAGB drug is not administered at a reduced frequency. 29. The method of claim 28,
Wherein each of the 1) the TKI drug or the AAGB drug and 2) the anti-ErB3 drug is administered at reduced frequency. 32. The method of claim 31,
Each reduced frequency is obtained by extending the intervals between administrations to at least one day. 33. The method according to any one of claims 21 to 32,
The anti-ErbB3 drug exhibits the first serum half-life;
The TKI drug or the AAGB drug exhibits a second serum half life; And
Administration to the patient of the anti-ErbB3 drug occurs within the first serum half-lives 1 to 3 times prior to administering the TKI drug or the AAGB drug;
Wherein the administration of the anti-ErbB3 drug occurs within second serum half-lives one to three times prior to administering the TKI drug or the AAGB drug. The method according to any one of claims 21 to 33, wherein
The ErbB3 drug is an anti-ErbB3 antibody. 35. The method of claim 34,
The anti-ErbB3 antibody is an antibody having a heavy chain sequence set forth in SEQ ID NO: 1 and a light chain sequence set forth in SEQ ID NO: 2. 34. The method of claim 33,
The anti-ErbB3 drug is a bispecific antibody comprising an anti-ErbB3 antibody linked with a second antibody. 36. The method according to any one of claims 21 to 36,
Wherein the AAGB drug is a basic compound. 37. The method according to any one of claims 21 to 37,
Wherein the AAGB drug is an anticancer agent. 39. The method according to any one of claims 21 to 38,
And the TKI drug is erlotinib or zefitinib. 35. The method according to claim 34 or 35,
The reduced dose for the anti-ErbB3 antibody is about 1/2 or about 1/4 of the monotherapy dose to the anti-ErbB3 antibody. 40. The method of claim 39,
The monotherapy dose for erlotinib is 150 mg / day and the reduced dose for erlotinib is 125 mg / day or 100 mg / day. 40. The method of claim 39,
The monotherapy dose for erlotinib is 150 mg / day and the reduced dose for erlotinib is 75 mg / day or 50 mg / day. 40. The method of claim 39,
The monotherapy dose for erlotinib is 100 mg / day and the reduced dose for erlotinib is 75 mg / day or 50 mg / day or 25 mg / day. 40. The method of claim 39,
The monotherapy dose for erlotinib is 150 mg / day and the reduced dose for erlotinib is 100 mg / day. 40. The method of claim 39,
The monotherapy dose for gefitinib is 250 mg / day, and the reduced dose for gefitinib is 150 mg / day or 125 mg / day or 100 mg / day; Or about 62 mg / day, or 50 mg / day. The method according to any one of claims 21 to 45,
The cancer may be breast cancer, ovarian cancer, kidney cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal cancer, lung cancer, prostate cancer, prostate epithelial tumor, sarcoma, melanoma, head and neck cancer, pancreatic cancer, gallbladder cancer, bladder cancer, brain and / or spinal cord. Cancer, gastric cancer, liver cancer, bone cancer, skin cancer, spleen cancer, testicular cancer, thyroid cancer, gastric cancer, and oral / pharyngeal cancer. A packaged formulation for treating cancer comprising an anti-ErbB3 drug in a pharmaceutically acceptable carrier and instructions for use according to the method of any of claims 21-45. A packaged formulation for treating cancer comprising an anti-ErbB3 antibody in a pharmaceutically acceptable carrier and instructions for use according to the method of any one of claims 21-45. The method according to any one of claims 21 to 45,
Wherein the patient is a smoker and the patient is given a modified dose of the TKI drug that is higher than a modified dose of TKI drug that would be given to the same patient if the same patient is a non-smoker. The method according to any one of claims 21 to 45,
Wherein the patient is a smoker and the dose of anti-ErbB3 drug is higher than a modified dose of anti-ErbB3 drug to be given to the same patient if the same patient is a non-smoker. 21. The method according to any one of claims 13 to 20,
Wherein the deformation is a reduction, and the warning indicates that the reduction for the patient who is a smoker should be of a smaller magnitude reduction than the reduction for the patient who is not a smoker.